ABSTRACT
A series of novel quinoline-oxadiazole hybrid compounds was designed based on stepwise rational modification of the lead molecules reported previously, in order to enhance bioactivity and improve druglikeness. The hybrid compounds synthesized were screened for biological activity against Mycobacterium tuberculosis H37Rv and for cytotoxicity in HepG2 cell line. Several of the hits exhibited good to excellent anti-tuberculosis activity and selectivity, especially compounds 12m, 12o and 12p, showed minimum inhibitory concentration values<0.5µM and selectivity index>500. The results of this study open up a promising avenue that may lead to the discovery of a new class of anti-tuberculosis agents.
Subject(s)
Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Animals , Antitubercular Agents/metabolism , Cell Survival/drug effects , Hep G2 Cells , Humans , Microbial Sensitivity Tests , Microsomes, Liver/metabolism , Oxadiazoles/metabolism , Quinolines/metabolism , Rats , Structure-Activity Relationship , Tuberculosis/drug therapyABSTRACT
A series of novel arylquinoline derivatives was designed retaining significant pharmacophoric features and three dimensional geometry of bedaquiline. In silico ADME study was performed to assess drug likeness and toxicity profiles of the designed molecules. The compounds were evaluated for activity against Mycobacterium tuberculosis H37Rv using Resazurin Microtitre Assay (REMA) plate method and cytotoxicity in VERO C1008 cell line. Several of the synthesized compounds exhibited good antituberculosis activity and selectivity, especially compounds, 12i (MIC: 5.18 µM and MIC/CC50: 152.86) and 12l (MIC: 5.59 µM and MIC/CC50: 160.57). The study opens up a new platform for the development of arylquinoline based drugs for treating tuberculosis.
